Inherited and acquired death receptor defects in human Autoimmune Lymphoproliferative Syndrome

The death receptor Fas/TNFRSF6 is a key player in lymphocyte apoptosis induction. Patients lacking a functional Fas/TNFRSF6 receptor develop a chronic lymphoproliferation termed Autoimmune LymphoProliferative Syndrome (ALPS), characterized by a benign tumoral syndrome, autoimmune cytopenias, hyperglobulinemia (G and A) and accumulation of TCRalphaBeta CD4-CD8- cells (called double-negative, or DN, T cells). Inherited mutations in the TNFRSF6 gene are responsible for most ALPS cases (ALPS-I). Caspase 10 gene mutations are found in a few of the remaining cases (ALPS-II). In a third group of patients (ALPS-III), somatic mosaicism of Fas/TNFRSF6 mutations as found in sporadic cases. Consequences of this finding will be discussed in terms of functional and molecular diagnosis as well as in the understanding of the pathophysiological basis of ALPS.